Cancerous cells often over-express certain proteases compared to normal cells. This has prompted efforts to target cancerous cells by linking a cytotoxic therapeutic agent to a peptide that a tumor protease cleaves, to release the cytotoxic drug proximate to or within cancerous cells while sparing or less substantially impacting normal cells.
U.S. Pat. No. 6,214,345 discloses tumor-specific peptide-drug conjugates that include a self-immolating linker and are selectively activated at the site of a tumor, wherein the drug may be mitomycin or doxorubicin, and the self-immolating linker is p-aminobenzyl alcohol.
Cells which express asparaginases make attractive targets for the peptide-drug conjugate approach, because many tumors over-express these proteases. One such asparaginase, legumain, has attracted particular attention in this connection (Wu et al., Cancer Research 2006; 66: 970-980; Liu et al., Cancer Research 2003; 63: 2957-2964; Bajjuri et al., ChemMedChem. 2011; 6:.doi: 10.1002/cmdc.201000478; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549592/pdf/ni hm 54-59 s-340268.pdf.).
Mitomycin, doxorubicin and camptothecin have attracted attention as drugs employed in peptide-drug conjugate therapies. U.S. Pat. No. 7,608,591; US Published Application 20110300147; US Published Application 20090175873; and U.S. Pat. No. 8,314,060 disclose examples of peptide-drug conjugates that target legumain with drugs that include doxorubicin.
Each of the above references is hereby incorporated by reference in its entirety.
These previous approaches have generally involved chemical modification of the drug moiety, which can adversely affect the drug's efficacy. Coupling of peptides directly (through the C-terminal carboxyl group) to the aziridine N atom of mitomycin yields a secondary amide, a functional group that typically is not subject to attack by proteases. Moreover, studies on mitomycin indicate the role of an NH group in the aziridine ring for biological activity. Thus there is a need for improved conjugates which target anti-tumor drugs such as mitomycin to tumor cells which express legumain and other asparaginases.